Hyperexcitability in hippocampal CA1 pyramidal cells OF Fmr1 knockout mice emerges during late postnatal development.

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder and the most frequent monogenic form of intellectual disability and autism. Fmr1 knockout (KO) mice have been used to study the neuronal bases of FXS. Alterations in both synaptic plasticity and electrophysiological membrane properties have been reported in young Fmr1 KO mice, but current knowledge about when and how these functional alterations emerge during postnatal development is almost lacking. To address this issue, we compared subthreshold and suprathreshold membrane properties at 8 to 28 postnatal days (P8-28) in pyramidal cells (PCs) of the dorsal CA1 hippocampus of wild-type- (WT) and Fmr1 KO-mice. Input resistance decreased with postnatal development, and significant differences between genotypes were found at P21-28. Action potential voltage threshold was significantly more negative at P21-28 in Fmr1 KO mice. Rheobase decreased with development in Fmr1 KO mice, and significant differences between genotypes were found at P21-28. Action potential firing frequency was significantly increased in Fmr1 KO mice at P21-28. All these parameters had no significant differences at P8-15. Firing frequency versus current intensity plot shifted to left in PCs from Fmr1 KO at P21-28, revealing that increased excitability was due to a rheobase decrease. Rheobase, in turn, depended on action potential voltage threshold. We conclude that CA1 PCs hyperexcitability from Frm1 KO mice was detectable at late postnatal development (P21-28), but not earlier (P8-15), and was due to a shifting of action potential voltage threshold to more hyperpolarized values.